Stress hyperglycemia increases short-term mortality in acute ischemic stroke patients after mechanical thrombectomy.

BACKGROUND AND PURPOSE: Glucose-to-glycated hemoglobin ratio (GAR) is considered a more reliable marker of stress hyperglycemia by correcting for basal blood glucose levels. This study aimed to investigate the extent to which GAR is associated with 3 month and 1 year all-cause mortalities in patients with acute ischemic stroke (AIS) undergoing mechanical thrombectomy (MT). METHODS: We retrospectively followed 553 AIS patients who underwent MT. The degree of stress hyperglycemia was quantified as the GAR, defined as fasting plasma glucose (mmol/L)/hemoglobin A1c (HbA1c) (%) on the second day after admission. According to the GAR quartiles, the patients were further categorized into four groups (group 1-group 4). We assessed the association between GAR and all-cause mortalities, clinical outcomes during hospitalization and function outcomes at 3 months. The associations between stress hyperglycemia and all-cause mortalities were analyzed using a Cox proportional-hazards model, while other outcomes were analyzed using multiple logistic regression analysis. RESULTS: The follow-up lasted a median of 18 months (range 0-66 months). The 3 month mortality rate was 9.58% (n = 53) and the 1 year mortality rate was 18.62% (n = 103). The Kaplan-Meier analysis revealed a significant inverse relationship between GAR and mortality (P < 0.001). In the Cox proportional-hazards model at 3 months, compared with group1, group 4 of GAR was associated with a significant increase in the risk of 3 month mortality (hazard ratio [HR] = 4.11, 95% confidence interval [CI] 1.41-12.0, P = 0.01) after adjusting for potential covariates. On multivariate logistic regression analysis, GAR was strongly associated with an increased risk of 3 month poor function outcome. CONCLUSIONS: Stress hyperglycemia, quantified by a higher GAR, is associated with all-cause mortality and poor functional outcomes in patients with AIS who undergo MT. Furthermore, GAR may contribute to improving the predictive efficiency of all-cause mortality in patients with AIS after MT, especially short-term all-cause mortality.

FUS-mediated HypEVs: Neuroprotective effects against ischemic stroke.

Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sEVs in the onset and progression of ischemic stroke remains an unresolved question. Our study systematically identified the characteristics of sEVs derived from neurons under hypoxic conditions (HypEVs) by physical characterization, sEV absorption, proteomics and transcriptomics analysis. The effects of HypEVs on neurites, cell survival, and neuron structure were assessed in vitro and in vivo by neural complexity tests, magnetic resonance imaging (MRI), Golgi staining, and Western blotting of synaptic plasticity-related proteins and apoptotic proteins. Knockdown of Fused in Sarcoma (FUS) small interfering RNA (siRNA) was used to validate FUS-mediated HypEV neuroprotection and mitochondrial mRNA release. Hypoxia promoted the secretion of sEVs, and HypEVs were more easily taken up and utilized by recipient cells. The MRI results illustrated that the cerebral infarction volume was reduced by 45% with the application of HypEVs, in comparison to the non- HypEV treatment group. Mechanistically, the FUS protein is necessary for the uptake and neuroprotection of HypEVs against ischemic stroke as well as carrying a large amount of mitochondrial mRNA in HypEVs. However, FUS knockdown attenuated the neuroprotective rescue capabilities of HypEVs. Our comprehensive dataset clearly illustrates that FUS-mediated HypEVs deliver exceptional neuroprotective effects against ischemic stroke, primarily through the maintenance of neurite integrity and the reduction of mitochondria-associated apoptosis.

Penumbra-targeted CircOGDH siRNA-loaded nanoparticles alleviate neuronal apoptosis in focal brain ischaemia.

BACKGROUND: Nanoparticles (NPs) are a class of substances that can be loaded with therapeutic agents delivered to specific areas. In our earlier research, we identified a neuron-derived circular RNA (circRNA), circular oxoglutarate dehydrogenase (CircOGDH), as a promising therapeutic target for acute ischaemic stroke. This study dedicated to explore a prospective preliminary strategy of CircOGDH-based NP delivered to the ischaemic penumbra region in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. METHODS: Immunofluorescence in primary cortex neurons and in vivo fluorescence imaging revealed endocytosis of Poly(lactide-co-glycolide) (PLGA) poly amidoamine(PAMAM)@CircOGDH small interfering RNA (siRNA) NPs. Western blotting analysis and CCK8 assay were performed to evaluate the apoptotic level in ischaemic neurons treated with PLGA-PAMAM@CircOGDH siRNA NPs. Quantitative reverse transcription PCR experiments, mice behaviour test, T2 MRI analysis, Nissl and TdT-mediated dUTP nick end labeling (TUNEL) co-staining were performed to evaluate the apoptosis level of ischaemic penumbra neurons in MCAO/R mice. Biosafety evaluation of NPs in MCAO/R mice was detected by blood routine examination, liver and kidney function examination and HE staining. RESULTS: PLGA-PAMAM@CircOGDH siRNA NPs were successfully assembled. Endocytosis of PLGA-PAMAM@CircOGDH siRNA NPs in ischaemic neurons alleviated neuronal apoptotic level in vitro and in vivo. Furthermore, mice behaviour test showed that the neurological defects of MCAO/R mice were significantly alleviated after the tail injection of PLGA-PAMAM@CircOGDH siRNA NPs, and no toxic effects were observed. CONCLUSION: In conclusion, our results suggest that PLGA-PAMAM@CircOGDH siRNA NPs can be delivered to the ischaemic penumbra region and alleviate neuron apoptosis in MCAO/R mice and in ischaemic neurons; therefore, our study provides a desirable approach for using circRNA-based NPs for the treatment of ischaemic stroke.

Spatial Proteomics Analysis of Soft and Stiff Regions in Human Acute Arterial Thrombus.

BACKGROUND: The soft regions of a thrombus tend to be more susceptible to r-tPA (recombinant tissue-type plasminogen activator)-mediated thrombolysis and are more easily removed by mechanical thrombectomy than the stiff counterpart. This study aimed to understand the molecular pathological differences between the soft and stiff regions of human arterial thrombus. METHODS: We developed a spatial proteomic workflow combining proteomics with laser-captured microdissection to analyze human arterial thrombi with Masson trichrome staining to identify stiff and soft regions from 2 independent cohorts of patients with acute myocardial or cerebral infarction. Dysregulated proteins in a C57BL6/J male mouse model of arterial thrombosis were identified by pathway enrichment and pairwise analyses from the common gene ontology enrichment and dysregulated proteins between carotid and coronary arterial thrombi, and validated by immunohistochemistry. RESULTS: Spatial proteomics of the coronary arterial thrombi collected from 7 patients with myocardial infarct revealed 7 common dysregulated proteins in 2 cohorts of patients, and upregulation of TGF-ß1 (transforming growth factor ß1) was the most prominent fibrosis-related protein. Inhibition of TGF-ß1 resulted in delayed arterial thrombosis and accelerated blood flow restoration in mouse model. We further expanded the spatial proteomic workflow to the carotid artery thrombi collected from 11 patients with cerebral infarction. Pairwise proteomic analysis of stiff and soft regions between carotid and coronary arterial thrombi further revealed 5 common gene ontology clusters including features of platelet activation, and a common dysregulated protein COL1A1 (collagen type 1 alpha 1) that was reported to be influenced by TGF-ß1. We also verified the expression in human and mice carotid arterial thrombi. CONCLUSIONS: This study demonstrates the spatially distinct composition of proteins in the stiff and soft regions of human arterial thrombi, and suggests that TGF-ß1 is a key therapeutic target for promoting arterial thrombolysis.

The association between stress hyperglycemia and unfavorable outcomes in patients with anterior circulation stroke after mechanical thrombectomy.

Background and purpose: Stress hyperglycemia is common in critical and severe diseases. However, few studies have examined the association between stress hyperglycemia and the functional outcomes of patients with anterior circulation stroke, after mechanical thrombectomy (MT), in different diabetes status. This study therefore aimed to determine the relationship between stress hyperglycemia and the risk of adverse neurological functional outcomes in anterior circulation stroke patients with and without diabetes after MT. Methods: Data of 408 patients with acute anterior circulation stroke treated with MT through the green-channel treatment system for emergency stroke at the First Affiliated Hospital of Jinan University between January 2016 and December 2020 were reviewed retrospectively. The stress hyperglycemia ratio (SHR) was calculated as fasting plasma glucose (mmol/L) divided by glycosylated hemoglobin (%). The patients were stratified into four groups by quartiles of SHR (Q1-Q4). The primary outcome was an excellent (nondisabled) functional outcome at 3 months after admission (modified Rankin Scale score of 0-1). The relationship between stress hyperglycemia and neurological outcome after stroke was assessed using multivariate logistic regression. Results: After adjusting for potential confounders, compared with patients in Q1, those in Q4 were less likely to have an excellent outcome at 3 months (odds ratio [OR], 0.32, 95% confidence interval [CI], 0.14-0.66, p = 0.003), a good outcome at 3 months (OR, 0.41, 95% CI, 0.20-0.84, p = 0.020), and major neurological improvement (OR, 0.38, 95% CI, 0.19-0.73, p = 0.004). Severe stress hyperglycemia increased risks of 3-months all-cause mortality (OR, 2.82, 95% CI, 1.09-8.29, p = 0.041) and ICH (OR, 2.54, 95% CI, 1.21-5.50, p = 0.015). Conclusion: Stress hyperglycemia was associated with a reduced rate of excellent neurological outcomes, and increased mortality and ICH risks in patients with anterior circulation stroke after MT regardless of diabetes status.

Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial.

OBJECTIVE: To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. METHODS: A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days. RESULTS: The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran-Mantel-Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). CONCLUSION: The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642.

Advances in Study of Chinese Medicine on Prevention and Treatment of Immune Response to Chronic Obstructive Pulmonary Disease / 中国实验方剂学杂志

Chronic obstructive pulmonary disease (COPD), as a common respiratory disease characterized by progressive development, not only has the incidence increased year by year, but also has a high disability and mortality rate, which brings serious economic burden to patients. Immune response plays an important role in the pathogenesis of COPD. Studies have shown that COPD is closely related to the disorder of autoimmune function, and traditional Chinese medicine (TCM) interferes with the disease process of COPD by mediating immune response. This paper mainly contains four kinds of research contents of TCM intervention on COPD immune response, namely T lymphocyte subsets count, immunoglobulin count, Th17/Treg dynamic balance, Th1/Th2 dynamic balance and related signaling pathways. In order to provide new reference and ideas for experimental research, a brief review is made at the end of this paper.

Breast reconstruction with a combined skin flap of DIEP and TRAM / 中华整形外科杂志

<p><b>OBJECTIVE</b>To evaluate breast reconstruction with a combined skin flap of the deep inferior epigastric perforator (DIEP) and the transverse rectus abdominis musculocutaneous (TRAM).</p><p><b>METHODS</b>The DIEP and TRAM united flap was elevated with the vessel pedicle of the deep inferior epigastric perforator on the affected side and the rectus abdominis muscle pedicle on the intact side. The reconstructive breast was shaped after the deep inferior epigastric vessels were anastomosed to the internal mammary vessels or the thoracodorsal vessels ipsilaterally.</p><p><b>RESULTS</b>We have used the DIEP and TRAM united flaps for breast reconstruction in 17 cases. All of the flaps survived, and the reconstructed breasts were well-shaped with the follow-up of 6-18 months.</p><p><b>CONCLUSIONS</b>The DIEP and TRAM united flap possesses of advantages such as rich blood supply, abundant tissue volume and easy shaping. It is especially applicable to the cases who have large chest defect and need large volume tissue.</p>